Erdheim-Chester disease is a rare, non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues by foamy histiocytes—that is, lipid-laden cells derived from the macrophage lineage. This multisystemic condition primarily affects the bones, retroperitoneum, heart, and aorta. Cardiovascular involvement, present in more than half of patients and frequently underdiagnosed, has a major impact on prognosis. Nearly 60% of patients carry the BRAF(V600E) mutation, a discovery that has opened up targeted therapeutic options. By contrast, the mechanisms underlying the formation of foamy histiocytes and their tissue infiltration remained poorly understood. The aim of this work was to determine whether an alteration in lipid metabolism contributes to lipid accumulation within histiocytes and to cardiovascular involvement.
Analysis of plasma lipids revealed that male patients carrying the BRAF(V600E) mutation displayed hypoalphalipoproteinemia, as evidenced by low HDL cholesterol concentrations. Moreover, serum from these patients exhibited a reduced capacity to promote free cholesterol efflux from human macrophages compared with controls. Cardiovascular involvement was detected in 84% of patients. Multivariate regression analysis identified the presence of the BRAF(V600E) mutation and hypoalphalipoproteinemia as independent determinants of aortic infiltration, alongside age; BRAF status emerged as a major contributing factor, with an odds ratio greater than 18, and 86% of mutation carriers showed cardiovascular infiltration.
Phenotyping of CD14+ blood cells, the precursors of histiocytes, made it possible to identify a specific inflammatory signature associated with aortic infiltration, partially modulated by the HDL phenotype. The authors propose that the reduction in the number and functionality of HDL contributes to aortic infiltration by activating these CD14+ cells, notably via the CXCL1 and CX3CR1 pathways, thereby promoting their recruitment into the aortic wall. Conversely, BRAF status did not appear to alter gene expression in CD14+ cells, suggesting that it acts on aortic infiltration through both HDL phenotype–dependent and –independent effects, the latter remaining to be characterized.
Finally, treatment with vemurafenib, an inhibitor of the BRAF(V600E) mutation, restored the impaired cholesterol efflux capacity of serum and reduced the aortic infiltration observed on computed tomography examinations. The authors emphasize that statins, which are effective on LDL cholesterol, do not correct hypoalphalipoproteinemia, and position vemurafenib as a first-line treatment in patients carrying the mutation. Overall, this study highlights the critical and independent role of hypoalphalipoproteinemia and of the BRAF(V600E) mutation in the aortic involvement of Erdheim-Chester disease.